Pesticide Found to Produce Parkinson's Symptoms in Rats

By SANDRA BLAKESLEE

Published: November 5, 2000

NEW ORLEANS, Nov. 4—
An organic pesticide widely used on home-grown fruits and vegetables and for killing unwanted fish in the nation's lakes and rivers produces all the classic symptoms of Parkinson's disease in rats that receive steady amounts of the chemical in their bloodstreams, scientists said today.

While it is much too soon to say that the pesticide, rotenone, causes or contributes to Parkinson's disease in humans, the scientists said the finding was the best evidence thus far that chemicals in the environment may be factors in this devastating disease.

Their study, the first to implicate rotenone in Parkinson's disease, was described here today at a workshop on the neurobiology of disease, held in conjunction with the annual meeting of the Society for Neuroscience, the nation's largest gathering of brain researchers. The workshop, sponsored by the National Institute of Neurological Disorders and Stroke, involved work carried out by Dr. Timothy Greenamyre and colleagues at Emory University in Atlanta. The results of the study will be published in the December issue of the journal Nature Neuroscience.

''This is a very important new study,'' said Dr. William Langston, president of the Parkinson's Institute, a leading center for research and treatment of the disease in Sunnyvale, Calif. ''It is the next major step in Parkinson's disease research.''

Dr. John Q. Trojanowski, an expert on neurodegenerative diseases at the University of Pennsylvania School of Medicine in Philadelphia and the moderator of the workshop, said, ''This is the best model we have ever had for this disease being associated with an environmental agent.''

But Dr. Trojanowski cautioned that the findings ''may not represent what anyone would experience in the real world.'' For one thing, the rats in the study were exposed to the chemical through their jugular veins, so it was not broken down or metabolized in the digestive tract. Still, Dr. Trojanowski said, the results are ''a major breakthrough'' and ''prompt us to look at how a lifetime exposure'' to a chemical or combination of chemicals might actually lead to Parkinson's disease.

Rotenone is extracted from the dried roots, seeds and leaves of various tropical plants, including the Jewel vine, derris and hoary pea. Like many plants that produce what are in effect their own pesticides, these plants apparently evolved to produce the compound as a way of warding off insects and other pests.

Rotenone is found in 680 compounds marketed as organic garden pesticides and flea powders, said Dr. Caroline Tanner, director of clinical research at the Parkinson's Institute. It is often sold as a white powder that is dusted onto roses, tomatoes, pears, apples and African violets, and even on household pets. It kills fire ants.

Because rotenone is naturally occurring, it is advertised as being safer than synthetic pesticides, she said. In addition, unlike many artificial pesticides, which linger in the environment, rotenone breaks down in five to six days of spring sunlight or two to three days of summer sunlight.

Rotenone is also widely used in liquid form by fishery managers to destroy pest species. The chemical is added to lakes and reservoirs, where it kills all the fish by inhibiting their ability to use oxygen. Once it has degraded, the water is restocked with the desired fish species.

Parkinson's disease is one of the most common neurodegenerative diseases, affecting nearly one million Americans over the age of 50. The disease is caused by the steady loss of cells, in a tiny region of the brain called the substantia nigra, that produce a chemical, dopamine, which is crucial for movement and cognition. Patients develop jerky, tremulous movements that get worse with time. Eventually they become entirely rigid.

A hallmark of the disease is that dopamine cells in the substantia nigra become clogged with tiny, gunky clumps of abnormal protein called Lewy bodies.

Scientists have suspected since the middle of the 19th century that an environmental toxin might be involved in Parkinson's disease, Dr. Tanner said. Moreover, people who work on farms or live in the countryside have as much as seven times as much risk of developing the disease as other people.

The first real clues to understanding the disease were found in 1983 when a number of young addicts using contaminated heroin developed severe Parkinson's-like symptoms. Researchers found that the drug had left dopamine-producing cells damaged much as they are damaged in Parkinson's disease and blocked the action of an important enzyme called complex one.

But mysteries remained. Why do dopamine-producing cells in just one tiny part of the brain die from lack of complex one, while other cells in the body and brain, including other dopamine-producing cells, are affected but do not necessarily shut down? And why were there no Lewy bodies?

Dr. Greenamyre, a professor of neurology and pharmacology at Emory, said he thought rotenone might offer a better model of the disease. It is a known complex one inhibitor, he said, and ''it is used in a zillion products.''

In the study, rats were given a steady low dose of rotenone directly into their bloodstreams for one to five weeks, Dr. Greenamyre said. The chemical could therefore pass more easily into the brain and not get broken down in the intestines. During the exposure, the rats grew stiff, stopped moving as much, hunched over and developed tremors -- just the kinds of problems that develop in Parkinson's disease.

''When we examined their brains we saw that they had a progressive degeneration of the dopamine system that goes awry in Parkinson's,'' Dr. Greenamyre said. ''It was extremely specific.'' And for the first time, scientists observed evidence of Lewy bodies.

But it remains to be seen if rotenone is a factor in human disease. Not everyone who uses it gets the disease. It may be one of many toxins that have to work in concert before Parkinson's will develop in the brain; rotenone alone may be relatively harmless for people.

Moreover, people may vary in their susceptibility to rotenone and similar chemicals, Dr. Greenamyre said.